N-(5-halo-2-thenyl)-substituted ethylene diamines



to tertiary amines of the formula:

Patented Jan. 8 1952 sTAre-s Para-NT. .oesercs .N-E (e-nsno-zdncnri.) sunsrrrurcn I ETHYL'ENE DIAMINES Lucas P. Kyrides, St. Louis, Mo., assignor to I Monsanto' Chemical Company, St. Louis, Mo., 3.

' corporation of Delaware No Drawing. Application August 11, 1947, H Serial No. 768,085

12 Claims. (01.260-296) This invention relates to new tertiaryamines of heterocyclicv compounds and more particularly RC--G-Rr, p R, R: 1 R4-4C --CHn-1 T-C.HrCHn-N S I i I i R3 in which R1 represents a radical selected from the group consisting of phenyl, pyridyl, and .picolinyl radicals; R2 represents a radical selected from the group consisting of hydrogen and alkyl radicalslcontaining 1-3 carbon atoms; R3 represents anealkyl radical containing l-3 carbon atoms; R4 represents a radical selected from the group consisting .of :chlorine andbromine; and R5 andRs each represent a radical selected from the group consisting of hydrogen and meth- "y'l radicals. When R1 is a pyridyl radical in the above formula, the respective isomeric pyridyl 'substituents, for example, the alphae'pyridyl, beta- 'pyri'dyl "and gamma-pyridyl 'substituents are'each contemplatedas being within the scope of the present invention. When R1 is a picolinyl radical in the above formula, the respectiveisomeric picolinyl substituentsfo'r example, in the case of the beta-picol-inyl radicaLthe alpha, alpha prime, beta primeand gamma substituents -and in the case of thealpha-picolinyl radical, the alpha prime, beta, beta .prime, and gamma substituents are contemplated. as being within the scope, of the present invention. 7 r

The compounds of "the present invention in which R2 and R3 are ethyl, n-propyl or isopropyl radicals, and R4 is-chlorine or bromine, may :be prepared, for example, by heating .-2- chloromethyl-5-ch1oro-;thiophene, 2-jchloromethyl-5-bromo-thiophene, 2-bromomethyl-5-chlorothiophene, or 2-bromomethyl 5-bromo-thiophene,

with a-benzene solution of an N-R1N,N-dialkyl thylenediam-ine'in which the alkyl radicals contain 2-3 carbon atoms and in whichR; is a substituent ofthe type defined hereinabove.

The compounds of the present invention (in which R2 and R3 are methyl radicals and R4 is .chlorine or bromine, may-be prepared by first preparing" the monohydrochloride of an N-R1--N,N'-dimethyl-ethylenediamine, for example, by refluxing abenzene solution of the diamine with an equivalent of ammonium chloride until evolution of ammonia ceases and subsequently .heating the monohydrochloride slurry thus formed with 5-chloromethyl-2-chloro-thiophene, 5-chloromethyl-2-bromo-thiophene, 5- bromomethyl-2-chloro-thiophene, or 5-bromomethy l-2-bromo thiophene.

N PPhenyI-N ',N' -dialky1-ethylenediamines and N-phenyl-Nealkyl-ethylenediamines for iause in the preparation ofxthe compoundswof-the .present invention may be prepared by heating 2 moles of aniline with 0.2 mole of the appropriate 'N-dialkyl-beta .chloroethylamine' hydrochloride present invention. The salts may be prepared by any suitable method,. for-example; by adding the appropriate acid or acidic agent, or a solution thereof in a suitable solvent, such as ether or toluene, to a solutionzof the free base product in a suitable solvent. The salt is then recovered from the solvent.

The new compounds-of the present invention are usefulas therapeutic agentsand more specifically as anti-histaminic agents. I

The following examples serve toill-ustrate' the invention without limiting it thereto.

Example I A mixtureof 186.2 grams (2 moles) of aniline and 28.8, grams (0.2 mole) of ,N,N-dimethyl-.betachloroethylamine hydrochloride was heated with stirring at100 ,C. for 2.hours, cooled'to 0., treated with 40 grams .of 50% sodium hydroxide solution and .40 cc. of water and stirredat '60" C. for one hour. Excess alkaliwas added. The

mixturewas stirred and the oil layer was separated and fractionated. Yieldof N-phenyl-N.., N- dimethylethylenediamine, 20.8 grams. Boiling point 117-118 C./8 mm. p

To a solution of. 26.6 grams of-N-phenyl-NQN- dimethylethylene'diamine in 100 .cc.' of benzene was added 8.7 gramsof ammonium. chloride and 0.5 cc. of water. The mixture was refluxed for 10 hours during whichtime ammonia was evolved. Themixturewas cooledto 30C., a solution of 13.5 grams .of .2echloromethyl-5-chloro-thiophene in 35 cc. of benzene was added and the mixture was heated at -70 C. for 5 hours.

.arated and washed with water.

S/ CHz I The product was dissolved in a mixture of carbon tetrachloride and acetone and to the solution was added dry hydrogen chloride sufiicient to form the monohydrochloride. The product obtained was N-phenyl-N-(5-chloro-2-theny1)- 'N,N' dimethyl ethylenediamine monohydrochloride. The product was recrystallized from acetone containing 4% water.

Example II I N-phenyl-N',N'-diethyl-ethylenediamine was prepared \fromaniline and N,N-diethyl-betachloroethylamine chloride, according to the procedure described in Example I. 'A solution of 23.0 g. (0.109 mole) of 2-chloromethyl-5-bromothiophenein 143 cc. of benzene was dropped into a solution of-4L9 grams (0.218 mole) of N,-phenyl-N',N'-diethyl-ethylenediamine in 218 cc. of butanol at room temperature in three hours. temperature for 19 hours.

of water and 8.7 cc. of 50% caustic soda solution were added andthe mixture was agitated for 45 minutes.

The mixture was then agitated at room Thereafter 100 ,cc.

The layers were separated and washed with .water. The benzene in butanol layer was distilled. The product obtained was N-phenyl-N- (5-bromo-2-thenyl) -N,N'-diethylethylenediamine having the formula:

S I C2115 The dihydrochloride salt was prepared in the manner described in Example I, using the appropriate amount of hydrogen chloride.

Example III To aslurry of sodamide in 200 cc. of toluene representing 7.1 grams of sodium was added at 30-40" C., 29.2 grams (0.31 mole) of 2-aminopyridine. The mixture was heated to reflux temperature and was refluxed for 1 hours.

'I'othe resulting mixture was added over a period ofapproximately 1 hour a solution of 32 grams of .freshly distilled N,N-dimethyl-beta-:chloroethylamine in 40-50 cc. of dry toluene. The re- A action mixture was then heated for 2- hours at reflux temperature. Thereafter, .200 cc. of water was added and the toluene layer was sep- The toluene was stripped from the mixture by distillation and the residue wasdistilled under reduced pressure.

.The distillate ,was refractionated and the por- A solution of 21.5 grams (0.13 mole) of N-(2'- thiophene.

4 pyridyl) -N',N'-dimethyl-ethylenediamine in 25 cc. of dry toluene was added to 3.2 grams of sodium hydride in cc. of toluene. The mixture was refluxed for one hour. To this mixture was added over a period of /Ig-hO'LlI a solution of 20 grams (0.12 hole) of 2-'ch1oromethyl-'5-chlorothiophene in 25 cc. of toluene; The resulting reaction mixture was refluxed for three hours. Thereafter, water was added and the toluene layer was separated and washed with water. The toluene was then stripped off by distillation and the residue was distilled under reduced pressure. The main fraction was redistilled. Yield of N-(2- pyridyl) -N-(5 chloro-2-theny1) N,N'-dimethy1- ethylenediamine having the formula:

' N HC--CH on;

g C1- -CH2-N-CH1-CH2-N s CH:

was 13.3 grams; boiling point -185" C./3 mm. A portion of the product was dissolved in a mixture of ether and methyl ethyl ketone, and an ether solution of hydrogen chloride was added. The monohydrochloride of N-(2-pyridyD-N-(5- chloro-Z-thenyl) -N',N -dimethylethylenediamine which separated was washed with ether and dried. v

The corresponding compound, N-(Z-pyridyD- N- (5 bromo-2-thenyl) -N ,N'-dimethyl-ethylenediamine having the formula:

. HC-CH 1 was prepared according to the method of the present example using 2-chloromethyl-5-bromothiophene in place of 2-chloromethyl-5-chloro- Likewise, the corresponding monohydrochloride of N-(Z-pyridyl) -N- (5-bromo-2- thenyl) N',N'-dimethyl ethylenediamine was prepared.

Example IV I The process of Example III was repeated using 32.3 grams of 3-amino-pyridine in place of 2- amino-pyridine in the preparation ofN-(3-pyridyl) N',N'-dimethyl ethylenediamine. The product thus obtained was then reacted with 2- bromomethyl-S-chlor0-thiophene in the manner described in Example III. A'portion of the resulting product, N-(B-pyridyl) N (5-chloro-2- thenyl) N',N'-dimethyl ethylenediamine, was converted to the monohydrochloride salt by the procedure described in Example III.

I Y Example? v The procedure of Example III was followed using 32.3 g. of 4-amino-pyridine in place of 2-amino-pyridine for the preparation of N-(-4- pyridyl)-N,N-dimethyl-ethylenediamine. This product was then reacted with 2-bromomethyl-5- bromo-thiophene according to the procedure of Example III for the preparation of N(4-pyridyl) -N- (5-bromo-2-thenyl) -N',N' -dimethyl ethylenediamine having the formula:

5. into the mononydrc'c'hlorid'ebytheprocedure de scribed in Example III.

Example V! "S? I "CH3 A portion of this product was converted to; the

.monohydrochloride by the .procedure described in Example III.

Example VII In place of 2-amino-pyridine in-ExampleIIL 33.5 grams of. 2amino+3-methylepyridine was employed in the preparation of N--2-betaepicolinyl) -N ,N -dimethyl-ethylenediamine according to the procedure of Example III. The product was then reacted with 2-chloromethyl-5-bromothiophene according to the procedure of Example Ill for the preparation of N-(Z-beta-picolinyl) -N- (5-bromo-2-thenyl) -N ,N' -diethyl ethylenediamine having the formula:

HC--CH (7H3 on;

Br-- CH2N-CH2-CHTN A portion of the resulting product was converted to the monohydrochloride by the procedure described in Example III.

Example VIII To a slurry of sodamide in 200 cc. of toluene representing 7.1 grams of sodium was added at 40 C. 29.2 grams of Z-amino-pyridine. The mixture was heated to reflux temperature and was refluxed for approximately 1 /2 hours. To the resulting mixture was added over a period of approximately one hour a solution of 37.5 grams of freshly distilled N-methyl-N-ethylbeta chloroethylamine in -50 cc. of dry toluene. The mixture was allowed to stand overnight. Thereafter, 200 cc. of water was added and the toluene layer was separated and washed with water. tion and the residue was distilled under reduced pressure. The distillate was refractionated and the product, N-(Z-pyridyl) -N'-methyl-N'-ethylethylenediamine was recovered.

A solution of 21.6 grams (0.121 mole) of N- (2 pyridyl) N methyl N ethyl-ethylenediamine in 25 cc. of toluene was added to a slurry of sodamide in 100 cc. of toluene representing The toluene was stripped off by distilla-.

6 washed with was The "toluene was then stripped 'oiT-by distillation- =andtheresidue was distilled by reduced pressure. The resulting product was N (2 pyridyl) N (5 chloro-2- thenyl) -N'- methyl -N'- -;ethyl-ethylenediamine having the formula:

0-1:- 0-oH2N-0Hz-oH-N S CH3 The "monohyd'rochloride of this product was'mbtained according the procedure "of Example In*amanalogous manner, the anti histamin'i'c agents of" the present invention in which R2- "is hydrogen-may "be prepared, using arr N -monoallqrl-jbeta4ililoroethylanriine, for example, N'- mono methyl beta-- chloroethylamine ermono-ethyl -beta-'chloro'ethyl'amine in place of an N,N-dialkyl=beta-chloroethylamine 'such as N,N-'dimethyl -"beta'*- chloroethylamine or NiN- diethyl beta-ch-loroethylamine.

The presentepplication is a continuation in part of my copending-application, Serial'Number 701.077 filed October 4, 1946".

I claim: 7 1. A compound from the group consisting of tertiary amines having the formula:

R,-c--0-R. R1 tar-( t d-om-N-onz-om-iv S R:

wherein R1 represents a radical selected from the group consisting of phenyl, pyridyl and picolinyl radicals, R2 represents a radical selected from 2.8 grams of sodium. The mixture was refluxed 3. An acid salt of the anti-histaminically active tertiary amine of the formula:

4. An acid salt of the anti-histaminically active tertiary amine of the formula:

Olin

5. The anti-histaminically active tertiary amine monohydrochloride salt of the formula:

H(|J(]3H (ll-37 1CHrN-OHz-CHz-N s CH:

26. The anti-histaminically active tertiary amine-monohydrochloride salt of the formula:

7. N,N dimethyl N (2 pyridyl) N'- (5-halo-2-thenyl) -ethylenediamines.

8. The method which comprises mixing together a 5-hal0-2-thenyl halide with analkali metal salt of N,N dimethyl N (2 pyridyl) ethylenediamine and heating the mixture in an inert solvent under substantially anhydrous conditions until a N,N-dimethyl-N'-(z-pyridyl) -N'- -(5-halo -2- thenyl) ethylenediamine is formed and recovering the said product.

9. An acid salt of an N,N-dimethyl-N'-(2- pyridyl) -N' (5-halo-2-thenyl) -ethylenediamine.

10. N,N dimethyl N (2 pyridyl) N (5- chloro-2-thenyl) -ethylenediamine.

11. N,N dimethyl N (2 phenyl) N'-- (5- chloro-Z-thenyl) -ethylenediamine.

12. A monohydrochloridesalt of the formula:

R5C-CRg R; R: I R-A OH -CH CH-N/ HCl I T" 2' I I 5 R; wherein R1 represents a radical selected from the group consisting of phenyl, pyridyl and picolinyl radicals, R2 represents a radical selected from the group consisting of hydrogen and alkyl radicals containing 1-3 carbon atoms, Ra represents an alkyl radical containing 1-3 carbon atoms, Rl'represents a halogen radical and R5 and Rs each represent a radical from the group consisting of hydrogen and methyl radicals.

- LUCAS P. KYRIDES.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Djerassi Aug. 27, 1946 OTHER REFERENCES Number 

1. A COMPOUND FROM THE GROUP CONSISTING OF TERTIARY AMINES HAVING THE FORMULA: WHEREIN R1 REPRESENTS A RADICAL SELECTED FROM THE GROUP CONSISTING OF PHENYL, PYRIDYL AND PICOLINYL RADICALS, R2 REPRESENTS A RADICAL SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND ALKYL RADICALS CONTAINING 1-3 CARBON ATOMS, R3 REPRESENTS AN ALKYL RADICAL CONTAINING 1-3 CARBON ATOMS, R4 REPRESENTS A HALOGEN RADICAL AND R5 AND R6 EACH REPRESENT A RADICAL FROM THE GROUP CONSISTING OF HYDROGEN AND METHYL RADICALS, AND THE ACID SALTS THEREOF 